Purification of tegaserod maleate

Abstract

Provided is a process for the purification of tegaserod maleate. Also provided is an isolated compound and the preparation thereof. This compound may be used as a reference marker and a reference standard, in the analysis of the purity of the tegaserod maleate.

1 . A method of purifying Tegaserod maleate comprising; 
 a) combining tegaserod maleate, a first organic solvent and an inorganic base to obtain a reaction mixture;    b) maintaining the reaction mixture at a temperature of from about room temperature to about the boiling temperature of the reaction mixture to obtain a precipitate;    c) combining the precipitate with a second organic solvent and a maleic acid with or without water at a temperature of from about room temperature to about the boiling temperature of the mixture; and    d) recovering the purified Tegaserod maleate.    
   
   
       2 . A method of purifying Tegaserod maleate comprising; 
 a) combining tegaserod maleate and a first organic solvent to obtain a reaction mixture;    b) combining the reaction mixture with an inorganic base and an organic carboxylic acid;    c) maintaining the reaction mixture obtained in step b) at a temperature of from about room temperature to about the boiling temperature of the reaction mixture to obtain a precipitate;    d) combining the precipitate with a second organic solvent and a solution of maleic acid, the second organic solvent, and water at a temperature of from about room temperature to about the boiling temperature of the mixture; and    e) recovering the purified Tegaserod maleate.    
   
   
       3 . The method of any one of claims  1  and  2 , wherein the reaction mixture is maintained at about room temperature.  
   
   
       4 . The method of  claim 1 , wherein the first organic solvent is a C 3 -C 7  ester.  
   
   
       5 . The method of  claim 4 , wherein the first organic solvent is selected from the group consisting of isobutyl acetate and ethyl acetate.  
   
   
       6 . The method of any one of claims  1  and  2 , wherein the inorganic base is in an aqueous solution.  
   
   
       7 . The method of  claim 2 , wherein the first organic solvent is selected from the group consisting of a C 1 -C 4  alcohol, a C 6 -C] 2  aromatic solvent, a C 1 -C 7  alkane or a C 2 -C 8  ether.  
   
   
       8 . The method of  claim 7 , wherein the first organic solvent is ethanol.  
   
   
       9 . The method of any one of claims  1  and 2, wherein the mixture of the first organic solvent and water is 1:1 volumes.  
   
   
       10 . The method of any one of claims  1  and  2 , wherein the amount of inorganic base added is 10 mol equivalents  
   
   
       11 . The method of any one of claims  1  and  2 , wherein the second organic solvent is selected from the group consisting of: a C 1 -C 8  alcohol, C 1 -C 4  ketones, C 1 -C 7  ethers, C 3 -C 7  esters, acetonitrile, dioxane and tetrahydrofuran.  
   
   
       12 . The method according to  claim 11 , wherein the second organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, butanol, acetone, dioxane, methylethyl ketone, tetrahydrofurane, ethyl lactate, and ethyl acetate.  
   
   
       13 . The method according to  claim 11 , wherein the second organic solvent is ethyl acetate.  
   
   
       14 . The method of  claim 1 , wherein the reaction mixture is maintained in step b) for a period of more than about 2 hours.  
   
   
       15 . The method of  claim 2 , wherein the reaction mixture is maintained in step c) for a period of more than about 5 hours.  
   
   
       16 . The method of  claim 2 , wherein the organic carboxylic acid of step b) has a pKa higher than about 2.  
   
   
       17 . The method of  claim 16 , wherein said organic carboxylic acid is acetic acid.  
   
   
       18 . The method of any one of claims  1  and  2 , wherein the precipitate is combined with the second organic solvent at a temperature of about room temperature to about 70° C.  
   
   
       19 . The method of any one of claims  1  and  2 , wherein combining the precipitate with a second organic solvent and a maleic acid is performed in the presence of water.  
   
   
       20 . The method of any one of claims  1  and  2 , wherein recovering of the purified tegaserod maleate comprises filtration.  
   
   
       21 . The method of any one of claims  1  and  2 , further comprising drying the purified tegaserod maleate.  
   
   
       22 . The method of any one of claims  1  and  2 , wherein the purified tegaserod maleate contains an amount of less than about 0.02% area by HPLC of the dimer impurity and of the impurities at RRT 2.01 and RRT 0.89.  
   
   
       23 . An isolated compound of the formula I;  
     
       
         
         
             
             
         
       
       wherein R is selected from the group consisting of: saturated and unsaturated branched and linear C 1 -C 4  alkanes, C 1 -C 4  ethers, C 1 -C 3  alcohols, C 6 -C 10  aromatic hydrocarbons and amides.  
     
   
   
       24 . The isolated compound of  claim 23 , wherein R is selected from the group consisting of: CH 2 OCH 3 , CH 2 CH═C(CH 3 ) 2 , CO—N(CH 3 ) 2 , CH 3 , C 2 H 5 , C 3 H 7 , benzoyloxy, CO-tert-C 4 H 9 , CO—N(C 2 H 5 ) 2 , CH 2 —CO—N(CH 3 ) 2 , CH 2 —CH 2 —N(CH 3 ) 2 , (CH 2 ) 2 —O—CH 3 , (CH 2 ) 2 —OH, isobutoxy, 2, 3-di(OH)-propoxy and acetoxy.  
   
   
       25 . The isolated compound of  claim 24 , wherein R is methyl.  
   
   
       26 . The isolated compound of  claim 25 , characterized by data selected from:  1 H NMR (500 MHz, DMSO d 6 ) δ(ppm): 11.73 (s, 2H), 8.53 (s, 2H), 7.89 (s, 4H), 7.75 (s, 2H), 7.37 (d, J=8.7 Hz, 2H), 6.87 (d, J=7.9 Hz, 2H), 3.87 (s, 6H); by  13 C{ 1 H}NMR analysis (125 MHz) δ (ppm): 154.83, 152.03, 146.32, 132.18, 124.76, 112.73, 112.65, 110.48, 104.41, 55.56; by FAB mass spectrometry analysis showing the following data: m/z=404.1 ([M−H] + , 100%) and by IR(KBr) ν cm −1 : 3385 (N—H), 2944 (C—H), 1641, 1637, 1613 (C═N), 1528, 1485 (C ar -C ar ).  
   
   
       27 . A method of using the isolated compound of  claim 25  as a reference marker.  
   
   
       28 . The method of  claim 27 , wherein the reference marker is an HPLC marker or an indicator for purity in a process.  
   
   
       29 . A method of using the isolated compound of  claim 25  as a reference standard.  
   
   
       30 . A method for preparing the isolated compound of  claim 23 , comprising the steps of; 
 a) mixing dianinoguanidine-HCl with water;    b) adding a compound of formula II;                          and an acid until a reaction mixture having a pH of about 2 to about 3 is obtained, wherein R is saturated and unsaturated, branched and linear C 1 -C 4  alkanes, C 1 -C 4  ethers, C 1 -C 3  alcohols, C 6 -C 10  aromatic hydrocarbons and amides;    c) maintaining the reaction mixture at a temperature from about room temperature to about boiling temperature of reaction mixture to obtain a precipitate; and    d) recovering a tegaserod derivative.    
   
   
       31 . The method of  claim 30 , wherein R is selected from the group consisting of: 
 CH 2 OCH 3 , CH 2 CH═C(CH 3 ) 2 , CO—N(CH 3 ) 2 , CH 3 , C 2 H 5 , C 3 H 7 , benzoyloxy, CO-tert-C 4 H 9 , CO—N(C 2 H 5 ) 2 , CH 2 —CO—N(CH 3 ) 2 , CH 2 —CH 2 —N(CH 3 ) 2 , (CH 2 ) 2 —O—CH 3 , (CH 2 ) 2 —OH, isobutoxy, 2,3-di(OH)-propoxy and acetoxy.    
   
   
       32 . The method of  claim 30 , wherein R is methyl.  
   
   
       33 . The method of to  claim 30 , wherein the acid is an inorganic acid selected from the group consisting of HCl, HBr, H 2 SO 4 , and H 3 PO 4 , or a carboxylic acid  
   
   
       34 . The method of to  claim 33 , wherein the acid is HCl.  
   
   
       35 . The method of  claim 30 , wherein the reaction mixture is maintained at about 70° C.  
   
   
       36 . A method for preparing crystalline forms tegaserod maleate having an amount of the impurity tegaserod dimer (TGS-dimer) of less than about 0.02% by area percent HPLC comprising; 
 a) obtaining one or more samples of one or more tegaserod maleate batches;    b) measuring the level of tegaserod dimer in each of the samples of (a);    c) selecting the tegaserod maleate batch that comprises a level of the tegaserod dimer of less than about 0.02% by area percent HPLC based on the measurement or measurements conducted in (b); and    d) using the batch selected in (c) to prepare said tegaserod maleate in crystalline form.    
   
   
       37 . A method of preparing a composition comprising crystalline form of TGS maleate, having TGS-dimer in an amount of less than about 0.02% by area percent HPLC, which method comprises; 
 a) purifying a composition comprising TGS maleate and TGS-dimer until a composition comprising less than about 0.02% TGS dimer by area percent HPLC is obtained; and    b) using the composition resulting from (a) to prepare a composition comprising a crystalline form of TGS maleate.    
   
   
       38 . The method according to  claim 37 , wherein the purifying a composition comprising tegaserod maleate and a tegaserod dimer is performed according to claims  1  or  2 .  
   
   
       39 . A method of preparing a composition comprising crystalline form of TGS maleate, having TGS-dimer in an amount of less than about 0.02% by area percent HPLC, which method comprises; 
 a) obtaining one or more samples of one or more TGS maleate batches;    b) measuring the level of TGS-dimer in each of the samples of (a);    c) if the quantity of the TGS-dimer measured in b) is about 0.02% area by HPLC or more, purifying the sample until the quantity of the TGS-dimer is less than about 0.02% by weight, and synthesizing a crystalline form of TGS maleate from the sample so purified; or    d) if the quantity of TGS-dimer measured in b) is less than about 0.02% by weight, synthesizing a crystalline form of TGS maleate from the TGS maleate of step b).    
   
   
       40 . The method according to  claim 39 , wherein the purifying a composition comprising tegaserod maleate and a tegaserod dimer is performed according to claims  1  or  2 .